This application seeks support for the continuation of an NICHD funded P01 Program Project at Baylor College of Medicine to study male infertility using state-of-the-art genetics. The Program Project has as its nucleus a core administrative unit that coordinates the activities of the basic and clinical scientists on a day-to-day basis. The areas of research focus of this Program Project are DNA repair defects in human non obstructive azoospermia and the consequences for children conceived by intracytoplasmic sperm injection (ICSI), the molecular control of spermatogonial cell proliferation in the testes, gene defects resulting in motility and sperm-egg interaction defects. These projects will benefit from the Tissue Procurement/Molecular Techniques Core for the analysis of large numbers of human samples from fertile and infertile men for the rapid clinical translation of the basic research findings. The overall aims for the proposal remain: To continue a Program Project Award for the study of male infertility that creates a close working relationship between basic and clinical scientists from the Departments of Urology, Obstetrics and Gynecology, Molecular and Cellular Biology, Pathology and Molecular Human Genetics. Facilitation of the close working relationships among these groups in one Program Project more effectively focuses on male infertility than would occur with these scientists working individually. To create a Tissue Procurement/Molecular Techniques facility that will provide well-characterized tissue from fertile and infertile men to investigators to rapidly translate the basic research findings to the clinical arena. The spontaneous, transgenic, and knock-out mouse models of male reproductive defects developed by Program Project investigators provide a significant and critical resource for eventual clinical translation. To correlate clinical features of male infertility with new discoveries at the molecular level, to better understand the disease processes and thereby develop new and more effective treatment and diagnostic modalities. The expertise of this multidisciplinary group of scientists working together is expected to yield new understandings of the basic pathophysiology of male infertility.